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Late developmental regulation in Chlamydia

衣原体的晚期发育调控

基本信息

批准号：
9978694
负责人：
Ming Tan
金额：
$ 44.99万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978694
关键词：
Active Sites Antibiotics Bacteria Binding Case Study Cells Centers for Disease Control and Prevention (U.S.)Chlamydia Chlamydia Infections Communicable Diseases Confocal Microscopy Cytoplasm DNA-Directed RNA Polymerase Development Dimerization Disease Notification Disulfides Enzyme Tests Escherichia coli Event Gene Expression Gene Expression Regulation Genes Genetic Transcription Glucose Goals Heterogeneity Human In Vitro Individual Infection Infectious Agent Interruption Late Gene Transcriptions Lead Membrane Molecular Target Oxidation-Reduction Oxides Oxidoreductase Pathway interactions Pattern Peptide Hydrolases Phosphoenolpyruvate Phosphoric Monoester Hydrolases Predisposition Production Proteolysis Public Health Quantitative Reverse Transcriptase PCR Regulation Regulatory Pathway Reporting Repression Role Sexually Transmitted Diseases Sigma Factor Signal Pathway Source Supplementation Testing Time Transcription Repressor Transcriptional Regulation chromatin immunoprecipitation derepression dimer disulfide bond enolase genital infection in vitro Assay in vivo monomer novel novel therapeutics premature prevent response therapeutic target transmission process

项目摘要

Project Summary/Abstract Chlamydia is one of the most important infectious agents from a public health perspective. In 2014 more than 1.4 million cases of chlamydial infections were reported to the CDC making it the most commonly reported infectious disease in the U.S. Chlamydia causes an unusual intracellular infection in which there are two specialized forms of the bacterium within an infected cell. The reticulate body (RB) is an intracellular form that replicates via multiple rounds of binary fission. Then at a late stage in the intracellular infection, each RB asynchronously converts into an elementary body (EB), which is the infectious form that transmits the infection to a new cell. We propose to study how this late developmental change from an RB to an EB is regulated by focusing on a small group of chlamydial genes that are upregulated at late times in the infection. We have evidence that these late genes are negatively regulated to prevent their premature expression. In Aim 1, we will study a transcriptional regulator called EUO to understand how its repression of late genes is relieved at late times to allow these genes to be expressed. We hypothesize that EUO is converted in a redox-dependent manner from a dimer into a monomer that is then degraded by proteolysis. In Aim 2, we will study another regulator called RsbW, which we propose is part of a signaling pathway that controls the transcription of a subset of late genes by σ28 RNA polymerase in response to glucose availability. Aim 3 will use confocal microscopy to examine these mechanisms of late gene regulation in individual RBs and EBs within a single infected cell. We will investigate whether the regulators of late gene expression also control RB- to-EB conversion and why this critical conversion step occurs asynchronously. These studies have the potential to lead to novel therapeutic strategies for treating chlamydial infections by interrupting this critical conversion step and preventing the production of infectious bacteria.

项目概要/摘要衣原体是公共卫生领域最重要的传染源之一看法。 2014年报告了超过140万例衣原体感染病例 CDC 使其成为美国最常报告的传染病衣原体引起一种不寻常的细胞内感染，其中有两种专门的感染受感染细胞内细菌的形式。网状体（RB）是细胞内的通过多轮二元裂变复制的形式。然后在后期阶段细胞内感染，每个RB异步转化为基本体（EB），这是将感染传播到新细胞的感染形式。我们建议研究这种从 RB 到 EB 的晚期发育变化是如何通过聚焦来调节的一小群衣原体基因在感染后期上调。我们有证据表明这些晚期基因受到负调控以防止它们的发生过早表达。在目标 1 中，我们将研究一种名为 EUO 的转录调节因子了解其对晚期基因的抑制如何在晚期解除，以允许这些基因来表达。我们假设 EUO 以依赖氧化还原的方式转化从二聚体变成单体，然后通过蛋白水解作用降解。在目标 2 中，我们将研究另一个称为 RsbW 的调节器，我们认为它是信号传导通路的一部分 σ28 RNA 聚合酶控制晚期基因子集的转录对葡萄糖可用性的反应。目标 3 将使用共焦显微镜来检查这些单个感染者中个体 RB 和 EB 的晚期基因调控机制细胞。我们将研究晚期基因表达的调节因子是否也控制 RB- 到 EB 转换以及为什么这个关键转换步骤异步发生。这些研究有可能带来治疗衣原体的新治疗策略通过中断这一关键的转化步骤并防止产生感染传染性细菌。